2-Methyl-1-nitropropane -Drug Synthesis Database

【结构式】

【分子编号】11782

【品名】2-Methyl-1-nitropropane

【CA登记号】

【分子式】C₄H₉NO₂

【分子量】103.121

【元素组成】C 46.59% H 8.8% N 13.58% O 31.03%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

The synthetic sequence used for the manufacture of ICI 200,880 is as follows: Carbodiimide-mediated coupling of acid (I) with amine (II) followed by ester hydrolysis with HCl affords acid (III). The other key intermediate, amino alcohol (VI), is prepared via alkylation of nitro-alkane (IV) with trifluoroacetaldehyde followed by reduction of the resulting nitro alcohol (V). Coupling of acid (III) with amino alcohol (VI) followed by oxidation with KMnO4 affords ICI 200,880. Since ICI 200,880 is an amorphous solid, it cannot be purified by crystallization. However, when acid (III) is purified by crystallization as its calcium salt and amino alcohol (VI) is purified by flash distillation, then the final coupling and oxidation proceed to yield ICI 200,880 of excellent purity.

参考文献中间体

合成目标

【1】 Edwards, P.D.; ICI 200880. Drugs Fut 1995, 20, 7, 662.
【2】 Bergeson, S.H.; Schwartz, J.A.; Stein, M.M.; Wildonger, R.A.; Edwards, P.D.; Shaw, A.; Trainor, D.A.; Wolanin, D.J. (AstraZeneca LP); Peptide derivs. AU 8652623; EP 0189305; ES 8706169; ES 8707551; ES 8802526; JP 1986218518; JP 1993246984; US 4910190; US 5055450; US 5194588 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	11780	4-([[(4-Chlorophenyl)sulfonyl]amino]carbonyl)benzoic acid	C₁₄H₁₀ClNO₅S	详情	详情
(III)	11781	(2S)-1-((2S)-2-[[4-([[(4-Chlorophenyl)sulfonyl]amino]carbonyl)benzoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid	C₂₄H₂₆ClN₃O₇S	详情	详情
(IV)	11782	2-Methyl-1-nitropropane	C₄H₉NO₂	详情	详情
(V)	11783	1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol	C₆H₁₀F₃NO₃	详情	详情
(VI)	11784	3-Amino-1,1,1-trifluoro-4-methyl-2-pentanol	C₆H₁₀F₃NO₃	详情	详情
(VII)	11785	(2S)-1-((2S)-2-[[4-([[(4-Chlorophenyl)sulfonyl]amino]carbonyl)benzoyl]amino]-3-methylbutanoyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)-2-pyrrolidinecarboxamide	C₃₀H₃₆ClF₃N₄O₇S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.

参考文献中间体

合成目标

【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	22770	tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate		C₂₂H₃₂N₂O₅	详情	详情
(III)	22671	4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride	100-07-2	C₈H₇ClO₂	详情	详情
(VII)	22776	(2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol		C₆H₁₂F₃NO	详情	详情
(X)	18168	1-iodo-2-methylpropane	513-38-2	C₄H₉I	详情	详情
(XI)	11782	2-Methyl-1-nitropropane		C₄H₉NO₂	详情	详情
(XII)	22781	2,2,2-trifluoro-1,1-ethanediol	421-53-4	C₂H₃F₃O₂	详情	详情
(XIII)	11783	1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol		C₆H₁₀F₃NO₃	详情	详情
(XIV)	22783	(2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol		C₆H₁₀F₃NO₃	详情	详情
(XV)	22784	(4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one		C₇H₁₀F₃NO₂	详情	详情
(XVI)	22785	(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate		C₁₈H₂₈F₃NO₄	详情	详情
(XVII)	22776	(2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol		C₆H₁₂F₃NO	详情	详情
(XVIII)	22787	(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid		C₁₈H₂₄N₂O₅	详情	详情
(XIX)	22788	benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate		C₂₄H₃₄F₃N₃O₅	详情	详情
(XX)	22789	(2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide		C₂₄H₃₄F₃N₃O₅	详情	详情

Extended Information